Calcium-Dependent Isoforms of Protein Kinase C Mediate Posttetanic Potentiation at the Calyx of Held

Fioravante, Diasynou; Chu, YunXiang; Myoga, Michael H.; Leitges, Michael; Regehr, Wade G.

doi:10.1016/j.neuron.2011.04.019

Cited by 44 publications

(103 citation statements)

References 69 publications

(169 reference statements)

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“…Although PMA potentiates release from embryonic chromaffin cells (21,30), potentiation persists after inhibition of PKC (22), deletion of Munc18-1 (30), or rescue of Syt1-KO with Syt T112A (21). In addition, the relative contribution of PKC to DAG-induced potentiation differs among synapses, as PKC activation is strictly required in hippocampal (6,8), but not in Calyceal synapses (7,11). This variation in PKC dependency is in line with the observation that a small population of cells did express potentiation after HFS in the absence of Syt1 phosphorylation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…High-frequency stimulation (HFS) transiently potentiates the EPSC amplitude, which requires activation of PKC (6,7,11). We therefore hypothesized that phosphorylation of Syt1 might be important for this form of STP.…”

Section: Phosphorylation Of Syt1 Enhances Potentiation After High-frementioning

confidence: 99%

“…4A). Paired-pulse plasticity critically depends on activation of Munc13-1 and PKC and PKC phosphorylation of Munc18-1, but Syt1 phosphorylation is dispensable (see above); potentiation by direct application of DAG (-analogs) depends on all these factors (8,11,12) and HFSinduced potentiation requires at least PKC activation (6,7,35), Munc18-1 phosphorylation (12), and Syt1 phosphorylation (Fig. 2), whereas the role of Munc13-1 is unknown.…”

Section: Potentiation Of Spontaneous Release Is Mediated By Multiple mentioning

confidence: 99%

“…The diacylglycerol (DAG)/protein kinase C (PKC) cascade is one of the most potent pathways at the presynaptic terminal. Its activation leads to 50-100% potentiation of spontaneous and action potential (AP)-evoked release (3)(4)(5), and is critical for multiple forms of presynaptic plasticity (6)(7)(8). DAG directly activates the vesicle priming factor Munc13-1 (9, 10) and indirectly activates downstream effectors via PKC.…”

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Phosphorylation of synaptotagmin-1 controls a post-priming step in PKC-dependent presynaptic plasticity

Jong

Meijer

Saarloos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Presynaptic activation of the diacylglycerol (DAG)/protein kinase C (PKC) pathway is a central event in short-term synaptic plasticity. Two substrates, Munc13-1 and Munc18-1, are essential for DAGinduced potentiation of vesicle priming, but the role of most presynaptic PKC substrates is not understood. Here, we show that a mutation in synaptotagmin-1 (Syt1 T112A ), which prevents its PKCdependent phosphorylation, abolishes DAG-induced potentiation of synaptic transmission in hippocampal neurons. This mutant also reduces potentiation of spontaneous release, but only if alternative Ca 2+ sensors, Doc2A/B proteins, are absent. However, unlike mutations in Munc13-1 or Munc18-1 that prevent DAG-induced potentiation, the synaptotagmin-1 mutation does not affect pairedpulse facilitation. Furthermore, experiments to probe vesicle priming (recovery after train stimulation and dual application of hypertonic solutions) also reveal no abnormalities. Expression of synaptotagmin-2, which lacks a seven amino acid sequence that contains the phosphorylation site in synaptotagmin-1, or a synaptotagmin-1 variant with these seven residues removed (Syt1 Δ109-116 ), supports normal DAG-induced potentiation. These data suggest that this seven residue sequence in synaptotagmin-1 situated in the linker between the transmembrane and C2A domains is inhibitory in the unphosphorylated state and becomes permissive of potentiation upon phosphorylation. We conclude that synaptotagmin-1 phosphorylation is an essential step in PKC-dependent potentiation of synaptic transmission, acting downstream of the two other essential DAG/PKC substrates, Munc13-1 and Munc18-1.P resynaptic strength changes rapidly during repetitive stimulation [short-term plasticity (STP)] and activation of intracellular signal transduction pathways (1, 2). The diacylglycerol (DAG)/protein kinase C (PKC) cascade is one of the most potent pathways at the presynaptic terminal. Its activation leads to 50-100% potentiation of spontaneous and action potential (AP)-evoked release (3-5), and is critical for multiple forms of presynaptic plasticity (6-8). DAG directly activates the vesicle priming factor Munc13-1 (9, 10) and indirectly activates downstream effectors via PKC. Activation of both Munc13-1 and PKC is essential for this pathway to operate (Fig. 1A) (8, 11). We previously identified Munc18-1 as an essential PKC substrate, because a nonphosphorylatable Munc18-1 mutant completely inhibits PKC-dependent STP (8, 12). Importantly, a phosphomimetic mutation of Munc18-1 cannot fully bypass the requirement for PKC activation, indicating that other PKC substrates must contribute to this form of plasticity (8). These substrates have not been identified to date.Among other presynaptic PKC substrates is synaptotagmin-1 (Syt1, ref. 13). Syt1 is the vesicular Ca 2+ sensor that mediates fast AP-evoked release in the hippocampus (14) and drives a large fraction of spontaneous release (15). In the latter case, Syt1 competes with alternative sensors, in particular Doc2s, for SNARE binding ...

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Section: Discussionmentioning

confidence: 99%

Section: Phosphorylation Of Syt1 Enhances Potentiation After High-frementioning

confidence: 99%

Section: Potentiation Of Spontaneous Release Is Mediated By Multiple mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Phosphorylation of synaptotagmin-1 controls a post-priming step in PKC-dependent presynaptic plasticity

Jong

Meijer

Saarloos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Mammalian Munc18 and the C. elegans homolog UNC-18 mediate signal-regulated NT and NP secretion by interacting with SNARE proteins and promoting the docking, priming, and exocytosis of synaptic vesicles (SVs) and DCVs (48)(49)(50)(51). In the calyx of Held auditory synapse, cPKCs transmit Ca 2ϩ and DAG signals by phosphorylating Ser or Thr in the 3a domain of Munc18 (13,(52)(53)(54)(55)(56). Phospho-Munc18 upregulates NT release by enhancing SV exocytosis.…”

Section: Pkc-2 Links Thermosensory Signals To Learned Behaviormentioning

confidence: 99%

A Calcium- and Diacylglycerol-Stimulated Protein Kinase C (PKC), Caenorhabditis elegans PKC-2, Links Thermal Signals to Learned Behavior by Acting in Sensory Neurons and Intestinal Cells

Land

Rubin

2017

Molecular and Cellular Biology

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Ca 2ϩ -and diacylglycerol (DAG)-activated protein kinase C (cPKC) promotes learning and behavioral plasticity. However, knowledge of in vivo regulation and exact functions of cPKCs that affect behavior is limited. We show that PKC-2, a Caenorhabditis elegans cPKC, is essential for a complex behavior, thermotaxis. C. elegans memorizes a nutrient-associated cultivation temperature (T c ) and migrates along the T c within a 17 to 25°C gradient. pkc-2 gene disruption abrogated thermotaxis; a PKC-2 transgene, driven by endogenous pkc-2 promoters, restored thermotaxis behavior in pkc-2 Ϫ/Ϫ animals. Cell-specific manipulation of PKC-2 activity revealed that thermotaxis is controlled by cooperative PKC-2-mediated signaling in both AFD sensory neurons and intestinal cells. Cold-directed migration (cryophilic drive) precedes T c tracking during thermotaxis. Analysis of temperature-directed behaviors elicited by persistent PKC-2 activation or inhibition in AFD (or intestine) disclosed that PKC-2 regulates initiation and duration of cryophilic drive. In AFD neurons, PKC-2 is a Ca 2ϩ sensor and signal amplifier that operates downstream from cyclic GMP-gated cation channels and distal guanylate cyclases. UNC-18, which regulates neurotransmitter and neuropeptide release from synaptic vesicles, is a critical PKC-2 effector in AFD. UNC-18 variants, created by mutating Ser 311 or Ser 322 , disrupt thermotaxis and suppress PKC-2-dependent cryophilic migration.KEYWORDS C. elegans signal integration, MUNC18 and UNC-18, calcium, diacylglycerol-activated PKC, cyclic GMP-gated channel, protein kinase C, regulation of learned behavior, sensory neuron, signal transduction, thermotaxis D iacylglycerol (DAG) and free cytoplasmic Ca 2ϩ mediate actions of hormones, neurotransmitters (NTs), and other stimuli that activate phospholipases C␤ and C␥ (1). Conventional protein kinase C isoforms (cPKCs ␣, ␤I, ␤II, and ␥) are widely expressed effectors of Ca 2ϩ and DAG in mammalian tissues (2-5). cPKCs are translocated to membranes and activated by binding Ca 2ϩ and DAG via their respective C2 and C1 domains. Thus, cPKCs are poised to receive, amplify, and disseminate the complete spectrum of intracellular signals generated by phospholipase C activation. Accordingly, cPKCs often couple extracellular stimuli to physiological processes that are coregulated by dynamic changes in Ca 2ϩ and DAG levels. In contrast, novel PKC isoforms (nPKCs ␦, , , and ) are activated by DAG alone.Some cell functions are redundantly regulated by combinations of PKCs. However, individual cPKCs can control key aspects of homeostasis or, when misregulated, promote pathological processes. For example, PKC␣ selectively regulates cardiac contrac-

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Synaptic plasticity in the auditory system: a review

2015

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Synaptic transmission via chemical synapses is dynamic, i.e., the strength of postsynaptic responses may change considerably in response to repeated synaptic activation. Synaptic strength is increased during facilitation, augmentation and potentiation, whereas a decrease in synaptic strength is characteristic for depression and attenuation. This review attempts to discuss the literature on short-term and long-term synaptic plasticity in the auditory brainstem of mammals and birds. One hallmark of the auditory system, particularly the inner ear and lower brainstem stations, is information transfer through neurons that fire action potentials at very high frequency, thereby activating synapses >500 times per second. Some auditory synapses display morphological specializations of the presynaptic terminals, e.g., calyceal extensions, whereas other auditory synapses do not. The review focuses on short-term depression and short-term facilitation, i.e., plastic changes with durations in the millisecond range. Other types of short-term synaptic plasticity, e.g., posttetanic potentiation and depolarization-induced suppression of excitation, will be discussed much more briefly. The same holds true for subtypes of long-term plasticity, like prolonged depolarizations and spike-time-dependent plasticity. We also address forms of plasticity in the auditory brainstem that do not comprise synaptic plasticity in a strict sense, namely short-term suppression, paired tone facilitation, short-term adaptation, synaptic adaptation and neural adaptation. Finally, we perform a meta-analysis of 61 studies in which short-term depression (STD) in the auditory system is opposed to short-term depression at non-auditory synapses in order to compare high-frequency neurons with those that fire action potentials at a lower rate. This meta-analysis reveals considerably less STD in most auditory synapses than in non-auditory ones, enabling reliable, failure-free synaptic transmission even at frequencies >100 Hz. Surprisingly, the calyx of Held, arguably the best-investigated synapse in the central nervous system, depresses most robustly. It will be exciting to reveal the molecular mechanisms that set high-fidelity synapses apart from other synapses that function much less reliably.

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Calcium-Dependent Isoforms of Protein Kinase C Mediate Posttetanic Potentiation at the Calyx of Held

Cited by 44 publications

References 69 publications

Phosphorylation of synaptotagmin-1 controls a post-priming step in PKC-dependent presynaptic plasticity

Phosphorylation of synaptotagmin-1 controls a post-priming step in PKC-dependent presynaptic plasticity

A Calcium- and Diacylglycerol-Stimulated Protein Kinase C (PKC), Caenorhabditis elegans PKC-2, Links Thermal Signals to Learned Behavior by Acting in Sensory Neurons and Intestinal Cells

Synaptic plasticity in the auditory system: a review

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